Novel Multitarget-Directed Ligands (MTDLs) with Acetylcholinesterase (AChE) Inhibitory and Serotonergic Subtype 4 Receptor (5-HT4R) Agonist Activities As Potential Agents against Alzheimer’s Disease: The Design of Donecopride

• Published in: Journal of medicinal chemistry Vol. 58; no. 7; pp. 3172 - 3187
• Main Authors: Rochais, Christophe, Lecoutey, Cédric, Gaven, Florence, Giannoni, Patrizia, Hamidouche, Katia, Hedou, Damien, Dubost, Emmanuelle, Genest, David, Yahiaoui, Samir, Freret, Thomas, Bouet, Valentine, Dauphin, François, Sopkova de Oliveira Santos, Jana, Ballandonne, Céline, Corvaisier, Sophie, Malzert-Fréon, Aurélie, Legay, Remi, Boulouard, Michel, Claeysen, Sylvie, Dallemagne, Patrick
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.04.2015; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Aniline Compounds - administration & dosage; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Chemical Sciences; Chemistry, Medicinal; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Computer Simulation; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical - methods; Guinea Pigs; Humans; Life Sciences & Biomedicine; Ligands; Male; Medicinal Chemistry; Memory, Short-Term - drug effects; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Pharmacology & Pharmacy; Piperidines - administration & dosage; Piperidines - chemistry; Piperidines - pharmacology; Receptors, Serotonin, 5-HT4 - metabolism; Science & Technology; Serotonin 5-HT4 Receptor Agonists - chemistry; Serotonin 5-HT4 Receptor Agonists - pharmacology; Structure-Activity Relationship; Toxicity Tests, Acute; MULTIPLE LIGANDS; BETA-AMYLOID AGGREGATION; IN-VITRO; MULTIFACTORIAL NATURE; LIPOIC ACID; SEARCH; DRUG DISCOVERY; GUINEA-PIG; GENETIC ALGORITHM; STRATEGIES; 5-HT4 Receptors; Donecopride; MTDL; Acetylcholinesterase; Alzheimer's Disease
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00115

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer’s disease.